hnRNP A18 is a RNA-binding protein that was first identified as a UV-inducible transcript in CHO cells more than two decades ago (Fornace et al., Proc Natl Acad Sci USA. 1988; 85(23):8800-8804). Since then, the hnRNP A18 protein has been characterized in human cells (Sheikh et al, J Biol Chem. 1997; 272(42):26720-26726) and in mouse following exposure to mild cold shock. hnRNP A18 is thus also known as CIRP for Cold Inducible RNA Binding Protein (Nishiyama et al. Gene. 1997; 204(1-2):115-120). Three hnRNP A18/CIRP mRNA transcripts, differing mainly in the size of their 5′ UTRs, have been described (Al-Fageeh M B and Smales C M., RNA. 2009; 15(6):1164-1176). The one we refer to as hnRNP A18 has the shortest 5′UTR and is expressed at 37° C. The two other transcripts are expressed at 32° C., harbor larger 5′UTRs and have shown internal ribosome entry segment (IRES)-like activity. hnRNP A18 is predominantly a nuclear protein but translocates to the cytoplasm in response to cellular stresses such as UV or hypoxia (Yang C and Carrier F., J Biol Chem. 2001; 276(50):47277-47284; Yang et al., J Biol Chem. 2010; 285(12):8887-8893). It is now becoming apparent that hnRNP A18 up-regulation is associated with a large number of solid tumors. In fact, immunohistochemistry staining of a variety of tumors from 193 patients indicate that hnRNP A18 is upregulated in about 30% of human tumors as compared to normal tissue from the same patients (Artero-Castro et al., Mol Cell Biol. 2009; 29(7):1855-1868). However, correlation with tumor grades or its potential tumor promoting activity in in vivo models has not been investigated so far.
Although a predominantly nuclear protein, hnRNP A18 has been located in the cytosol of several tumor cells (Artero-Castro et al., Mol Cell Biol. 2009; 29(7):1855-1868). This observation is consistent with the fact that most solid tumors develop hypoxic regions, mainly in the central core of the tumor, and that hnRNP A18 translocates to the cytosol in response to hypoxia (Harris A L., Nat Rev Cancer. 2002; 2(1):38-47; Wellmann et al., J Cell Sci. 2004; 117(Pt 9):1785-1794; Yang et al., J Biol Chem. 2010; 285(12):8887-8893). Earlier studies have revealed that hnRNP A18 translocation to the cytosol is mediated, in part, by the hypoxia inducible GSK-3βkinase and CK2 (Yang et al., Nucleic Acids Res. 2006; 34(4):1224-1236; Yang et al., J Biol Chem. 2010; 285(12):8887-8893). GSK-3βalso increases hnRNP A18 RNA binding activity and both, hnRNP A18 RNA binding domain and the RGG domain are required for maximal hnRNP A18 RNA binding activity (Yang et al., Nucleic Acids Res. 2006; 34(4):1224-1236). In the cytosol, hnRNP A18 binds to a specific 51 nucleotide RNA signature motif present in the 3′UTR of targeted transcripts and increases their translation by interacting with eukaryotic initiation factor 4G (eIF4G), a component of the general translation cap-binding complex eIF4F, on polysomes (Pamboukian R C F., Molecular and Cellular Pharmacology. 2012; 4:41-48; Yang et al., Nucleic Acids Res. 2006; 34(4):1224-1236; Yang et al., J Biol Chem. 2010; 285(12):8887-8893).
This background information is provided for informational purposes only. No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present invention.